Project Summary/Abstract Healthy human intestines contain over 1000 different bacterial species and 1014 bacterial cells - roughly ten times the number of human cells in the body. Inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, is thought to result from an inappropriate inflammatory response by the immune system against bacteria in our intestines, or in the case of celiac disease, against food constituents. An important mechanism of maintaining immune tolerance to food and commensals in the intestines is the development of peripheral CD4+ regulatory T cells (pTregs). Dendritic cells in the intestinal lamina propria are essential for acquiring antigens from the gut lumen and stimulating the differentiation and proliferation of pTregs. We have identified a gut dendritic cell transmembrane protein, CD101, that is specifically expressed on a subset of DCs involved in pTreg cell development. Moreover, we have preliminary data showing that CD101 plays an important role in the proper differentiation of pTregs in the gut. This proposal will extend these intriguing preliminary findings on the role of CD101 in the differentiation of pTregs. In Aim 1, we will investigate whether global loss of CD101 expression impacts differentiation of different T cell subsets in the intestine, including pTregs, Th1, Th2, and Th17 cells. We will examine the numbers of T cell subsets within the gut both at homeostasis and inflammation as well as examine the differentiation of peripherally transferred clonal nave T cells in CD101 deficient mice. In Aim 2, we will determine whether loss of CD101 on dendritic cells is sufficient to impair pTreg differentiation in the intestines. In Aim 3, we will test whether cytokine production by dendritic cells, localization of dendritic cells, antigen uptake by dendritic cells, and direct modulation of dendritic cell-T cell interactions and signaling are impaired in CD101 knockout mice. These results may determine the importance and mechanism by which CD101 influences pTreg differentiation and may lead to the development of novel therapeutics to treat inflammatory diseases of the intestines.